| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy and safety of once daily (evening) administration of FF/VI 100/25 with FF 100 in adult and adolescent subjects ≥ 12 years of age with moderate to severe, persistent bronchial asthma over 12 weeks. |
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| E.2.2 | Secondary objectives of the trial |
| To assess the relative efficacy of Fluticasone Furoate/Vilanterol 200/25mcg and Fluticasone Furoate/Vilanterol 100/25. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.Informed consent: Subjects must give their signed and dated (written) informed consent to participate.
Written informed consent must be obtained if a subject’s current medication is changed as a result of study participation (e.g., withholding of albuterol for FEV1 measurements or withholding of LABA on the day of Visit 1) and the subject will be required to return to the clinic to complete the screening visit once the required wash-out has been completed.
2.Type of Subject: Subjects must be outpatients ≥12 years of age at Visit 1 who have had a diagnosis of asthma, as defined by the National Institutes of Health, for at least 12 weeks prior to Visit 1. Countries with local restrictions prohibiting enrolment of adolescents will only enroll subjects ≥18 years of age.
3.Gender: Subjects may be male or an eligible female.
Eligible female is defined as having non-childbearing potential or having childbearing potential and using an acceptable method of birth control consistently and correctly. The following is the GSK list of acceptable, highly effective methods for avoiding pregnancy with failure rates of less than 1% per year:
a.Abstinence from penile-vaginal intercourse, when this is the female’s preferred and usual lifestyle
b.Oral Contraceptive, either combined or progestogen alone
c.Injectable progestogen
d.Implants of etonogestrel or levonorgestrel
e.Estrogenic vaginal ring
f.Percutaneous contraceptive patches
g.Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label
h.Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.
i.Male condom combined with a female diaphragm either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)
4.Severity of Disease: Subjects must have a best pre-bronchodilator FEV1 of 40%-80% of their predicted normal value.
Predicted values will be based upon NHANES III. The equations for the predicted values are:
•The Caucasian equation will be used unless the subject is of Hispanic or Latino, African-American, or Asian descent,
•If a subject is of Hispanic or Latino ethnicity, then the Mexican-American equations will be used irrespective of race.
•If a subject is of African-American/African race, then the African-American equations will be used.
•If a subject is of Asian race, then the Asian adjustment will be used.
5.Reversibility of Disease: Subjects must demonstrate ≥12% and ≥200mL reversibility of FEV1 within 10-40 minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol (or an equivalent nebulized treatment with albuterol/salbutamol solution) or have documented reversibility testing within the 6 months prior to Visit 1 meeting this measure of reversibility. A spacer device may be used for testing, if required.
6.Asthma Therapy Prior to Visit 1:
Subjects are eligible if they have received ICS for at least 12 weeks prior to Visit 1 and their treatment during the 4 weeks immediately prior to Visit 1 consisted of either of the two regimens (a or b) below (Figure 2 of the protocol). Acceptable ICS and ICS/LABA doses for the 4 weeks immediately prior to Visit 1 are described in the Study Procedure Manual.
a.A stable mid-dose or high-dose of ICS alone (e.g., ≥ FP 250 mcg twice daily) or
b.A stable dose of a mid-dose ICS/LABA combination (e.g., FP/Salmeterol [SALM] 250/50 mcg twice daily) or an equivalent combination via separate inhalers.
7.Short-Acting Beta2-Agonists (SABAs): All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1 for use as needed, per product label, for the duration of the study. Subjects must be able to withhold albuterol/salbutamol for at least 6 hours prior to study visits. |
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1.History of Life-threatening Asthma: Defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years.
2.Respiratory Infection: Culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is:
a.not resolved within 4 weeks of Visit 1 and led to a change in asthma management or,
b.in the opinion of the investigator, expected to affect the subject’s asthma status or the subject’s ability to participate in the study.
3.Asthma Exacerbation: Any asthma exacerbation that
a.required oral corticosteroids within the 12 weeks prior to Visit 1 or
b.resulted in an overnight hospitalization requiring additional treatment for asthma within 6 months prior to Visit 1.
4.Concurrent Respiratory Disease: A subject must not have current evidence of
a.Atelectasis (segmental or larger)
b.Bronchopulmonary dysplasia
c.Chronic obstructive pulmonary disease including chronic bronchitis and emphysema
d.Pneumonia
e.Pneumothorax
f.Pulmonary fibrotic disease
g.Or any evidence of concurrent respiratory disease other than asthma
5.Other Concurrent Diseases/Abnormalities:A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study.
6.Viral Hepatitis: Subjects with chronic stable hepatitis B or C are acceptable provided their screening alanine transaminase (ALT) is <2x upper limit of normal (ULN) and the subject otherwise meets the entry criteria. Subjects who have chronic co-infection with both hepatitis B and hepatitis C are not eligible.
7.Oral Candidiasis: A subject will not be eligible if he/she has clinical visual evidence of candidiasis at Visit 1.
8.Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1 or within five half-lives (t½) of the prior investigational study, whichever is longer of the two.
9.Allergies:
a.Drug Allergy: Any adverse reaction, including immediate or delayed hypersensitivity, to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy or known or suspected sensitivity to the constituents of the NDPI (i.e., lactose or magnesium stearate)
b.Milk Protein Allergy: History of severe milk protein allergy
10.Concomitant Medication: Administration of prescription or non-prescription medication that would significantly affect the course of asthma, or interact with study drug, such as anticonvulsants (barbiturates, hydantoins, carbamazepine), polycyclic antidepressants, beta-adrenergic blocking agents, phenothiazines, and monoamine oxidase (MAO) inhibitors
11.Immunosuppressive Medications: A subject must not be using or require use of immunosuppressive medications during the study.
12.Cytochrome P450 3A4 (CYP3A4) Inhibitors: Subjects who have received a potent CYP3A4 inhibitor within 4 weeks of Visit 1 are ineligible. (See SPM for listing of strong CYP3A4 inhibitors).
13.Compliance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, disease, or resides in a geographical location which seems likely, in the opinion of the Investigator, to impair compliance with any aspect of this study protocol, including visit schedule, and completion of the daily diaries.
14.Tobacco Use: Current smoker or has a smoking history of 10 pack-years (20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products within the past 3 months (i.e., cigarettes, cigars, or pipe tobacco).
15.Affiliation with Investigator’s Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
16.Previous Phase III Study Participation: A subject previously randomized to treatment with FF/VI or FF in another Phase III study cannot participate.
17.Night Shift Workers: Subjects who have performed night shift work during the week prior to Visit 1 are not eligible for the study. No night shift work is allowed during the entire study period.
18.Children in Care: Adolescents who are wards of the state or government are not eligible for participation in this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Weighted mean serial FEV1 over 0-24 hours post-dose at the end of the 12 week treatment period.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Pre-dose, post-dose assessments at 5, 15, and 30 minutes and at 1, 2, 3, 4, 5, 12, 16, 20, 23 and 24 hours. |
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| E.5.2 | Secondary end point(s) |
•Change from baseline in clinic visit trough FEV1
•Change from baseline in the percentage of rescue-free 24-hour periods
•Change from baseline in the percentage of symptom-free 24-hour periods
•Change from baseline in AM PEF
•Change from baseline in PM PEF |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Change from baseline in clinic visit trough FEV1: at the end of the 12 week treatment period
•Change from baseline in the percentage of rescue-free 24-hour periods: during the 12-week treatment period
•Change from baseline in the percentage of symptom-free 24-hour periods: during the 12-week treatment period
•Change from baseline in AM PEF: averaged over the 12-week treatment period
•Change from baseline in PM PEF: averaged over the 12-week treatment period
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Fluticasone Furoate 100 mcg |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Germany |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Sweden |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the last subject's last visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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